SUMMARY/ABSTRACT Mental illnesses are the largest source of healthcare utilization costs in the US, and the costliest of non- communicablediseasesworldwide?estimatedtoresultin$6Trillioninannualsocietalburdenby2030.The way in which we have defined psychiatric diagnoses (i.e. based only on symptom clusters) and identified treatments (i.e. capitalizing on serendipity), has failed to substantially mitigate the disabling burden of these diseases,whichtypicallyappearearlyinlifeandpersist.Notsurprisingly,individualpsychiatricdiagnosesare highly clinically and biologically heterogeneous, with as much or greater variability within a diagnosis as between diagnoses. The number of mechanistically distinct psychiatric drug targets has also not grown in decades, and typically only half of patients respond well in clinical trials. Public stigma towards psychiatric disorders remains palpable, as lay understanding of the brain bases of these conditions contrasts with the growing excitement amongst scientists for the potential of grounding diagnosis and treatment directly in neurobiology.Neuroimaging,asthedominanttoolinhumanneuroscience,however,hasbeenusedlargelyfor comparing these arbitrarily-defined diagnoses against healthy individuals not for robustly characterizing individualpatientsinobjectivebiologicalterms.Imagingisalsoapurelyobservationalmethod,andthuscannot byitselfprovidethecausalunderstandingofcircuitrythatisnecessaryfortransitioningfromadescriptivetoa circuit-based mechanistic understanding of mental illness that can directly guide novel interventions. Here, I propose a new diagnostic and treatment development framework that transcends the arbitrariness and heterogeneity of traditional diagnoses, the limitations of group-level imaging analyses and current trial-and- error approaches to treatment planning. Rather, this ?Circuits-First? platform focuses on understanding causalityinthebraincircuitsofindividualpatientsasameansforpersonalizeddiagnosisandtreatmentusing individually-tailoredplasticity-inducingneurostimulation,establishingdirectlinkagebetweencircuitsandclinical outcome. Successful implementation of this ?Circuits-First? approach will establish a platform for rapid translation to other psychiatric disorders, and beyond to specific neurological disorders (e.g. stroke, Parkinson?s)wherecircuitperturbationsareprominent.Importantly,despiteitsnovelty,myapproachwillcreate areadilyscalableplatformthat,withsimplemodifications,canhavethepotentialtotransformclinicalpractice in the near term. This is facilitated by the use of broadly-applicable, already FDA-approved tools (e.g. transcranial magnetic stimulation (TMS) and electroencephalography (EEG)), and the fact that it can be performed in the office-based settings of the clinical practitioner, thus not restricted to specialized research labs.